Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries.However,a key challenge is the cellular source for transplantation which is often limited by donor availab...Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries.However,a key challenge is the cellular source for transplantation which is often limited by donor availability.Direct reprogramming provides an exciting avenue to generate specialized neuron subtypes in vitro,which have the potential to be used for autologous transplantation,as well as generation of patient-specific disease models in the lab for drug discovery and testing gene therapy.Here we present a detailed review on transcription factors that promote direct reprogramming of specific neuronal subtypes with particular focus on glutamatergic,GABAergic,dopaminergic,sensory and retinal neurons.We will discuss the developmental role of master transcriptional regulators and specification factors for neuronal subtypes,and summarize their use in promoting direct reprogramming into different neuronal subtypes.Furthermore,we will discuss up-and-coming technologies that advance the cell reprogramming field,including the use of computational prediction of reprogramming factors,opportunity of cellular reprogramming using small chemicals and microRNA,as well as the exciting potential for applying direct reprogramming in vivo as a novel approach to promote neuro-regeneration within the body.Finally,we will highlight the clinical potential of direct reprogramming and discuss the hurdles that need to be overcome for clinical translation.展开更多
The human retina is a specialized multilayered structure composed of numerous cell types.The process of vision relies on a robust network integrated by rod photoreceptors,cone photoreceptors,bipolar cells,horizontal c...The human retina is a specialized multilayered structure composed of numerous cell types.The process of vision relies on a robust network integrated by rod photoreceptors,cone photoreceptors,bipolar cells,horizontal cells,amacrine cells and retinal ganglion cells,which detect,process and relay the visual information to the brain.Additionally,structural and metabolic support is provided by Muller glia,retinal astrocytes and microglia.Over 200 genes have been implicated in inherited retinal diseases(RetNet:https://sph.uth.edu/retnet/).However,in many cases,the retinal cell types that express these disease-associated genes remain to be identified.The complexity of the human retina represents a major challenge for the molecular profiling of all retinal cell types.Many previous studies utilised bulk RNA-seq to profile the whole human adult retina,which only analysed the averaged gene expression levels across all retinal cell types.As such,knowledge of the transcriptome profile in specific cell types within the retina would help us to unravel the heterogeneity of retinal cells,advance understanding of the pathogenesis of inherited retinal diseases,and to develop gene therapies that could improve treatment options.展开更多
基金Supported by funding from the Ophthalmic Research Institute of Australia,the University of Melbourne De Brettville Trustthe Kel and Rosie Day Foundationthe Centre for Eye Research Australia
文摘Cell therapy offers great promises in replacing the neurons lost due to neurodegenerative diseases or injuries.However,a key challenge is the cellular source for transplantation which is often limited by donor availability.Direct reprogramming provides an exciting avenue to generate specialized neuron subtypes in vitro,which have the potential to be used for autologous transplantation,as well as generation of patient-specific disease models in the lab for drug discovery and testing gene therapy.Here we present a detailed review on transcription factors that promote direct reprogramming of specific neuronal subtypes with particular focus on glutamatergic,GABAergic,dopaminergic,sensory and retinal neurons.We will discuss the developmental role of master transcriptional regulators and specification factors for neuronal subtypes,and summarize their use in promoting direct reprogramming into different neuronal subtypes.Furthermore,we will discuss up-and-coming technologies that advance the cell reprogramming field,including the use of computational prediction of reprogramming factors,opportunity of cellular reprogramming using small chemicals and microRNA,as well as the exciting potential for applying direct reprogramming in vivo as a novel approach to promote neuro-regeneration within the body.Finally,we will highlight the clinical potential of direct reprogramming and discuss the hurdles that need to be overcome for clinical translation.
基金RCBW was supported by funding from the University of Melbourne,Centre for Eye Research Australia,Retina Australia and the National Health and Medical Research Council(APP1184076).
文摘The human retina is a specialized multilayered structure composed of numerous cell types.The process of vision relies on a robust network integrated by rod photoreceptors,cone photoreceptors,bipolar cells,horizontal cells,amacrine cells and retinal ganglion cells,which detect,process and relay the visual information to the brain.Additionally,structural and metabolic support is provided by Muller glia,retinal astrocytes and microglia.Over 200 genes have been implicated in inherited retinal diseases(RetNet:https://sph.uth.edu/retnet/).However,in many cases,the retinal cell types that express these disease-associated genes remain to be identified.The complexity of the human retina represents a major challenge for the molecular profiling of all retinal cell types.Many previous studies utilised bulk RNA-seq to profile the whole human adult retina,which only analysed the averaged gene expression levels across all retinal cell types.As such,knowledge of the transcriptome profile in specific cell types within the retina would help us to unravel the heterogeneity of retinal cells,advance understanding of the pathogenesis of inherited retinal diseases,and to develop gene therapies that could improve treatment options.
